Secondary hyperparathyroidism (SHPT, secondary hyperparathyroidism) refers to a chronic compensatory clinical manifestation in which parathyroid glands are stimulated by hypocalcemia, hypomagnesemia, or hyperphosphatemia for a long-term to secrete excessive parathyroid hormone (PTH) to increase blood calcium, blood magnesium and reduce blood phosphorus in the case of chronic renal insufficiency, intestinal malabsorption syndrome, Fanconi syndrome and renal tubular acidosis, vitamin D deficiency or resistance, as well as pregnancy, lactation, etc. Long-term parathyroid hyperplasia eventually leads to the formation of functionally autonomous adenomas.
Etelcalcetide is a novel calcimimetic agent developed by Kai Pharmaceuticals, Inc., which can inhibit the secretion of parathyroid hormone (PTH). Secondary hyperparathyroidism (SHPT) is a common and severe decompensation disorder in patients with chronic kidney disease (CKD) undergoing dialysis treatment. It is currently known that persistently elevated parathyroid hormone (PTH) is associated with a key clinical outcome in patients with CKD. Etelcalcetide can bind to and activate calcium-sensing receptors on the parathyroid glands to reduce parathyroid hormone (PTH) levels.
Etelcalcetide consists of three D-configuration arginines, two D-configuration alanines, one D-configuration argininamide, one D-configuration cysteine, and one L-configuration cysteine (the N-terminus is blocked by acetyl), wherein the D-configuration cysteine and the L-configuration cysteine are linked together by a disulfide bond (N-acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-Argininamide, disulfide with L-cysteine), the structure of which is shown below:

Patent CN201080045024.9 first reported this compound, but no synthesis process of the compound was reported. The key to the synthesis of this compound lies in the construction of intermolecular disulfide bonds. The conventional intermolecular disulfide bond construction generally requires the purification and preparation of two peptide fragments, followed by activation of one of the sulfydryl groups, then reaction with another sulfydryl group to form a disulfide bond after purification and preparation, and finally purification of the corresponding products obtained after the preparation. However, the reaction steps of the method are relatively tedious, requiring multi-step purification for preparation, the production cost is correspondingly high, and the final total yield is low.